tbuckley/cabot-search huggingface dataset:
Age Differences in Effects of Sacubitril/Valsartan on Cardiac Remodeling, Biomarkers, and Health Status
Authors: Sean P. Murphy, Jonathan H. Ward, Ileana L. Piña, G. Michael Felker, Javed Butler, Alan S. Maisel, Xiangyi Meng, Margaret F. Prescott, Scott D. Solomon, James L. Januzzi
Journal: JACC Heart Failure (2022)

Sacubitril/valsartan (Sac/Val) improves outcomes in patients with heart failure with reduced ejection fraction (HFrEF).In this study, the authors sought to explore age differences in effects of Sac/Val on biomarkers, Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores and cardiac remodeling.After initiation and titration of Sac/Val, concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-cTnT), and soluble suppressor of tumorigenicity 2 (sST2) were measured and KCCQ-23 scores obtained from baseline to 12 months. Left ventricular ejection fraction (LVEF), and indexed left ventricular end-systolic (LVESVi) and indexed left ventricular end-diastolic (LVEDVi) and left atrial volume index (LAVi) volumes were measured with the use of echocardiography. Safety end points were assessed. Age-stratified analysis was performed for groups aged <65, 65-74, and ≥75 years.Among 794 participants with HFrEF (mean age 65.1 years, 28.5% women), compared with patients aged <65 years (n = 369), 65-74 years (n = 237), and those aged ≥75 years (n = 188), had similar reductions in hs-cTnT and sST2, but less NT-proBNP reduction (-45.6% vs -40.2% vs -30.5%, respectively; P = 0.02). Gains in KCCQ-23 were smaller (+11.8 vs +11.4 vs +6.0 points; P = 0.03) in patients aged ≥75 years, although similar proportions of each age group achieved ≥10-point and ≥20-point increases in KCCQ-23 by month 12. Improvements in LVEF, LVEDVi, LVESVi, and LAVi were similar among age groups. Incidence of safety end points was also similar.Sac/Val resulted in significant improvements in prognostic biomarkers and measures of cardiac remodeling and health status from baseline to month 12 across age categories. Older study participants showed somewhat blunted reduction in NT-proBNP and less improvement in KCCQ-23 overall summary scores. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling, and Outcomes [PROVE-HF]; NCT02887183).
A generally minimalist strategy of constructing biomineralized high-efficiency personalized nanovaccine combined with immune checkpoint blockade for cancer immunotherapy
Authors: Sijia Zhang, Yuanji Feng, Meng Meng, Zhen Li, Huixin Li, Lin Lin, Caina Xu, Jie Chen, Kai Hao, Zhaohui Tang, Huayu Tian, Xuesi Chen
Journal: Biomaterials (2022)
Short-course versus long-course antibiotic treatment for uncomplicated vancomycin-resistant enterococcal bacteraemia: a retrospective multicentre cohort study
Authors: Christina Bahrs, Siegbert Rieg, Annette Hennigs, Florian Hitzenbichler, Thomas T Brehm, Norman Rose, Rebecca J Jacobi, Valerie Heine, Daniel Hornuss, Gunnar Huppertz, Stefan Hagel, Frank Hanses
Journal: Clinical Microbiology and Infection (2022)
The High Mutational Sensitivity of <i>ccdA</i> Antitoxin Is Linked to Codon Optimality
Authors: Soumyanetra Chandra, Kritika Gupta, Shruti Khare, Pehu Kohli, Aparna Asok, Sonali Vishwa Mohan, Harsha Gowda, Raghavan Varadarajan
Journal: Molecular Biology and Evolution (2022)

Deep mutational scanning studies suggest that synonymous mutations are typically silent and that most exposed, nonactive-site residues are tolerant to mutations. Here, we show that the ccdA antitoxin component of the Escherichia coli ccdAB toxin-antitoxin system is unusually sensitive to mutations when studied in the operonic context. A large fraction (∼80%) of single-codon mutations, including many synonymous mutations in the ccdA gene shows inactive phenotype, but they retain native-like binding affinity towards cognate toxin, CcdB. Therefore, the observed phenotypic effects are largely not due to alterations in protein structure/stability, consistent with a large region of CcdA being intrinsically disordered. E. coli codon preference and strength of ribosome-binding associated with translation of downstream ccdB gene are found to be major contributors of the observed ccdA mutant phenotypes. In select cases, proteomics studies reveal altered ratios of CcdA:CcdB protein levels in vivo, suggesting that the ccdA mutations likely alter relative translation efficiencies of the two genes in the operon. We extend these results by studying single-site synonymous mutations that lead to loss of function phenotypes in the relBE operon upon introduction of rarer codons. Thus, in their operonic context, genes are likely to be more sensitive to both synonymous and nonsynonymous point mutations than inferred previously.
Genetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation
Authors: Sylvan C. Baca, Cassandra Singler, Soumya Zacharia, Ji-Heui Seo, Tunc Morova, Faraz Hach, Yi Ding, Tommer Schwarz, Chia-Chi Flora Huang, Jacob Anderson, André P. Fay, Cynthia Kalita, Stefan Groha, Mark M. Pomerantz, Victoria Wang, Simon Linder, Christopher J. Sweeney, Wilbert Zwart, Nathan A. Lack, Bogdan Pasaniuc, David Y. Takeda, Alexander Gusev, Matthew L. Freedman
Journal: Nature Genetics (2022)
RNA m6A regulates transcription via DNA demethylation and chromatin accessibility
Authors: Shuang Deng, Jialiang Zhang, Jiachun Su, Zhixiang Zuo, Lingxing Zeng, Kaijing Liu, Yanfen Zheng, Xudong Huang, Ruihong Bai, Lisha Zhuang, Ying Ye, Mei Li, Ling Pan, Junge Deng, Guandi Wu, Rui Li, Shaoping Zhang, Chen Wu, Dongxin Lin, Jianjun Chen, Jian Zheng
Journal: Nature Genetics (2022)
Benzodiazepines and Withdrawal Psychosis
Authors: Sheldon H. Preskorn
Journal: JAMA (1977)

Three cases of acute psychotic illness following sudden withdrawal from high daily doses of benzodiazepines were associated with agitation and confusion. Disorientation was prominent in two of the patients. None of the patients had had previous psychotic episodes. The condition of all patients was reversed dramatically with hypnotic drugs. Gradual withdrawal was successfully accomplished without relapse, with a follow-up of as much as one year. To our knowledge, this is the first such series in the literature. (<i>JAMA</i>237:36-38, 1977)
Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Jocelyn McCullough, Rohan G Perera
Journal: New England Journal of Medicine (2022)

A 59-year-old woman was admitted to the hospital with unheralded syncope. An electrocardiogram showed epsilon waves, and an echocardiogram showed a severely dilated right ventricle (shown in a video).
Progress toward Better Treatment of Lupus
Authors: Daniel J. Wallace
Journal: New England Journal of Medicine (2022)

Systemic lupus erythematosus (SLE) is an inflammatory, multisystem autoimmune disease of unknown cause that has protean clinical and laboratory manifestations along with a variable course and prognosis.1 Approximately 200,000 patients in the United States currently meet the diagnostic criteria for lupus, but up to 500,000 have features that fall on a spectrum that overlaps with that of lupus, such as both undifferentiated and mixed connective-tissue disease and antiphospholipid syndrome. Lupus is associated with multiple complications and is one of the leading causes of death in young women.2 In those between the ages of 15 and 24 years, it is the . . .
Case 27-2022: A 32-Year-Old Man with Confusion, Headache, and Fever
Authors: Nagagopal Venna, Pamela W. Schaefer, Eli M. Miloslavsky
Journal: New England Journal of Medicine (2022)

A 32-year-old man with Behçet's disease was admitted after 2 weeks of confusion and headache and 2 days of fever. CSF analysis showed lymphocyte-predominant pleocytosis and a low glucose level. A diagnosis was made.
Convalescent Plasma for Covid-19
Authors: David J Sullivan, Kelly A Gebo, Daniel F Hanley
Journal: New England Journal of Medicine (2022)

In their editorial regarding the article by Sullivan et al. (May 5 issue), 1 Estcourt and Callum 2 note the inconsistent benefits of convalescent plasma for the treatment of Covid-19.However, they overlook the reproducible nature of the findings of numerous randomized, controlled trials and analyses of real-world data, which have shown that the use of convalescent plasma reduces the incidence of hospitalization and death when a sufficient dose is given to patients with a recent onset of symptoms and to those who do not have a sufficient antibody response to SARS-CoV-2 infection. 3 Trials that have shown negative results have often included patients who were too sick to benefit or who received convalescent plasma with low antibody levels. 4 In addition, Sullivan et al. found that the efficacy of convalescent plasma was similar to that of monoclonal antibodies, although the latter are susceptible to viral escape.In this context, higher-titer convalescent plasma obtained from vaccinated or recovered donors should be comparatively resistant to viral escape. 5
Closed-Loop Therapy and Preservation of C-Peptide Secretion in Type 1 Diabetes
Authors: Charlotte K. Boughton, Janet M. Allen, Julia Ware, Malgorzata E. Wilinska, Sara Hartnell, Ajay Thankamony, Tabitha Randell, Atrayee Ghatak, Rachel E.J. Besser, Daniela Elleri, Nicola Trevelyan, Fiona M. Campbell, Judy Sibayan, Peter Calhoun, Ryan Bailey, Gareth Dunseath, Roman Hovorka
Journal: New England Journal of Medicine (2022)

Whether improved glucose control with hybrid closed-loop therapy can preserve C-peptide secretion as compared with standard insulin therapy in persons with new-onset type 1 diabetes is unclear.In a multicenter, open-label, parallel-group, randomized trial, we assigned youths 10.0 to 16.9 years of age within 21 days after a diagnosis of type 1 diabetes to receive hybrid closed-loop therapy or standard insulin therapy (control) for 24 months. The primary end point was the area under the curve (AUC) for the plasma C-peptide level (after a mixed-meal tolerance test) at 12 months after diagnosis. The analysis was performed on an intention-to-treat basis.A total of 97 participants (mean [±SD] age, 12±2 years) underwent randomization: 51 were assigned to receive closed-loop therapy and 46 to receive control therapy. The AUC for the C-peptide level at 12 months (primary end point) did not differ significantly between the two groups (geometric mean, 0.35 pmol per milliliter [interquartile range, 0.16 to 0.49] with closed-loop therapy and 0.46 pmol per milliliter [interquartile range, 0.22 to 0.69] with control therapy; mean adjusted difference, -0.06 pmol per milliliter [95% confidence interval {CI}, -0.14 to 0.03]). There was not a substantial between-group difference in the AUC for the C-peptide level at 24 months (geometric mean, 0.18 pmol per milliliter [interquartile range, 0.06 to 0.22] with closed-loop therapy and 0.24 pmol per milliliter [interquartile range, 0.05 to 0.30] with control therapy; mean adjusted difference, -0.04 pmol per milliliter [95% CI, -0.14 to 0.06]). The arithmetic mean glycated hemoglobin level was lower in the closed-loop group than in the control group by 4 mmol per mole (0.4 percentage points; 95% CI, 0 to 8 mmol per mole [0.0 to 0.7 percentage points]) at 12 months and by 11 mmol per mole (1.0 percentage points; 95% CI, 7 to 15 mmol per mole [0.5 to 1.5 percentage points]) at 24 months. Five cases of severe hypoglycemia occurred in the closed-loop group (in 3 participants), and one occurred in the control group; one case of diabetic ketoacidosis occurred in the closed-loop group.In youths with new-onset type 1 diabetes, intensive glucose control for 24 months did not appear to prevent the decline in residual C-peptide secretion. (Funded by the National Institute for Health and Care Research and others; CLOuD ClinicalTrials.gov number, NCT02871089.).
On the Path toward Expanding Treatment Options for Diabetes
Authors: Sue A. Brown
Journal: New England Journal of Medicine (2022)

Achieving glycemic goals, particularly in patients with type 1 diabetes, is an ongoing challenge that has been met, in part, with a variety of device-related solutions. Recent advancements in diabetes management have included the development of automated insulin delivery (AID) devices, also referred to as closed-loop or artificial pancreas systems. Several such systems have been validated in clinical trials in both children and adults with type 1 diabetes and are commercially available in several countries. Across age ranges, these trials have shown consistently improved glycemic outcomes, including lower glycated hemoglobin values, lower frequencies of hypoglycemia and hyperglycemia, and improvement in . . .
Trial of Anti-BDCA2 Antibody Litifilimab for Systemic Lupus Erythematosus
Authors: Richard A. Furie, Ronald F. van Vollenhoven, Kenneth Kalunian, Sandra Navarra, Juanita Romero-Diaz, Victoria P. Werth, Xiaobi Huang, George Clark, Hua Carroll, Adam Meyers, Cristina Musselli, Catherine Barbey, Nathalie Franchimont
Journal: New England Journal of Medicine (2022)

Antibody-binding of blood dendritic cell antigen 2 (BDCA2), which is expressed exclusively on plasmacytoid dendritic cells, suppresses the production of type I interferon that is involved in the pathogenesis of systemic lupus erythematosus (SLE). The safety and efficacy of subcutaneous litifilimab, a humanized monoclonal antibody that binds to BDCA2, in patients with SLE have not been extensively studied.
Open-Source Automated Insulin Delivery in Type 1 Diabetes
Authors: Mercedes J. Burnside, Dana M. Lewis, Hamish R. Crocket, Renee A. Meier, Jonathan A. Williman, Olivia J. Sanders, Craig A. Jefferies, Ann M. Faherty, Ryan G. Paul, Claire S. Lever, Sarah K.J. Price, Carla M. Frewen, Shirley D. Jones, Tim C. Gunn, Christina Lampey, Benjamin J. Wheeler, Martin I. de Bock
Journal: New England Journal of Medicine (2022)

Open-source automated insulin delivery (AID) systems are used by many patients with type 1 diabetes. Data are needed on the efficacy and safety of an open-source AID system.
CLOuDs Disperse — Top-Notch Glucose Control and Residual C-Peptide Secretion
Authors: Jan Bolinder
Journal: New England Journal of Medicine (2022)

Type 1 diabetes results from autoimmune destruction of insulin-producing beta cells, yet many patients retain endogenous beta-cell function several years after clinical onset — some for decades, as evidenced by persistent C-peptide secretion.1 Residual C-peptide secretion has been associated with substantial clinical benefits. For example, data from the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications follow-up study showed that among DCCT participants who entered the trial within 1 to 5 years after diabetes onset and had a C-peptide response (defined as a mixed meal–stimulated C-peptide peak response of ≥0.2 pmol per milliliter) at . . .
Rebound of SARS-CoV-2 Infection after Nirmatrelvir–Ritonavir Treatment
Authors: Michael E Charness, Kalpana Gupta, Gary Stack, Judith Strymish, Eleanor Adams, David C Lindy, Hiroshi Mohri, David D Ho
Journal: New England Journal of Medicine (2022)

Rebound of SARS-CoV-2 Infection after Nirmatrelvir-Ritonavir TreatmentTo the Editor: Nirmatrelvir is an inhibitor of the main protease in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has been shown to block viral replication and reduce disease severity in unvaccinated persons at risk for the progression of coronavirus disease 2019 . 1 Here, we describe the occurrence of rebound symptoms and viral replication after treatment with nirmatrelvir combined with ritonavir.Patient 1, a 71-year-old man with asthma, reported having rhinorrhea, sore throat, congestion, cough, fatigue, malaise, chills, fever (temperature, 38.4°C), and a positive rapid antigen test for SARS-CoV-2.A 5-day course of nirmatrelvirritonavir was started on the same day.He was asymptomatic from day 2 through day 8. On days 9 through 12, while the patient was still isolating, he had a return of typical cold symptoms with rhinorrhea, sore throat, and congestion along with increased asthma symptoms.SARS-CoV-2 viral load was determined from anterior nasal swabs according to the cycle threshold (Ct) on quantitative reverse-transcriptasepolymerase-chain-reaction (RT-PCR) assay and indirectly from results of antigen testing.Peaks of symptoms and viral load coincided on days 1 and 9 (Fig. 1 and Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).Whole-genome viral sequencing identified the BA.1.20subvariant of the SARS-CoV-2 B.1.1.529(omicron) variant from day 1 through day 11.Patient 2, a 69-year-old man, had cold symptoms and positive results on rapid antigen testing and PCR assay on day 0 through day 3.A 5-day course of nirmatrelvir-ritonavir was started on day 1.The patient was asymptomatic with negative results on rapid antigen testing and intermittent PCR assays from day 4 to day 9. Mild cold symptoms and positive results on both rapid antigen testing and RT-PCR assay recurred on day 10 and lasted for 3 days.Patient 3, a 50-year-old woman who lived in the same household with Patient 2, had a similar pattern of rebound symptoms and viral load after treatment with nirmatrelvir-ritonavir.Viral sequencing identified the omicron BA.2.9 subvariant in these two patients.In all three patients who have been described here, there were no muta-The New England Journal of Medicine Downloaded from nejm.org
Durability of Booster mRNA Vaccine against SARS-CoV-2 BA.2.12.1, BA.4, and BA.5 Subvariants
Authors: Panke Qu, Julia N Faraone, John P Evans, Yi-Min Zheng, Lianbo Yu, Qin Ma, Claire Carlin, Gerard Lozanski, Linda J Saif, Eugene M Oltz, Richard J Gumina, Shan-Lu Liu
Journal: New England Journal of Medicine (2022)

To the Editor: Mounting concern about the long-term efficacy of messenger RNA (mRNA) booster vaccines against coronavirus disease 2019 (Covid-19) 1 has been exacerbated by the recent emergence of the B.1.1.529(omicron) subvariants BA.2.12.1 and BA.4 and BA.5 (hereafter, BA.4/5) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which have high degrees of immune escape. 2 To address this concern, we used our previously reported pseudotyped lentivirus neutralization assay (see the Supplementary Appendix, available with the full text of this letter at NEJM.org) to examine neutralizing-antibody titers against major SARS-CoV-2 variants in a longitudinal cohort of health care workers from the Ohio State University Wexner Medical Center in Columbus who had received homologous vaccine and booster doses of an mRNA vaccine.A total of 24 participants received the mRNA-1273 vaccine (Moderna), and 22 received the BNT162b2 vaccine (Pfizer-BioNTech).We classified participant samples into three groups according to the timing of booster-dose administration: 1 to 3 months, 4 to 6 months, and 7 to 9 months before the sample was obtained (Table S1 in the Supplementary Appendix).Over the course of the study, 14 participants had a breakthrough infection; 9 cases occurred during the omicron waves.Booster durability waned more substantially in participants who did not have breakthrough infection than in those who had breakthrough infection, with neutralizing-antibody titers, presented as 50% neutralization titers (NT 50 ), against all variants at 1 to 3 months after the booster dose being approximately 1.7 times
Efficacy of Antiviral Agents against the Omicron Subvariant BA.2.75
Authors: Emi Takashita, Seiya Yamayoshi, Shuetsu Fukushi, Tadaki Suzuki, Ken Maeda, Yuko Sakai-Tagawa, Mutsumi Ito, Ryuta Uraki, Peter Halfmann, Shinji Watanabe, Makoto Takeda, Hideki Hasegawa, Masaki Imai, Yoshihiro Kawaoka
Journal: New England Journal of Medicine (2022)

Efficacy of Antiviral Agents against the Omicron Subvariant BA.2.75To the Editor: Five sublineages of the B.1.1.529(omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) -BA.1, BA.2, BA.3, BA.4, and BA.5 -are recognized, and BA.5 is currently the predominant variant circulating globally. 1In India and Nepal, however, the prevalence of a subvariant of BA.2 (designated BA.2.75) is increasing rapidly and is now becoming dominant in Nepal. 2 Moreover, BA.2.75 has been detected in at least 25 other countries, including the United States, Singapore, Canada, the United Kingdom, Japan, and Australia; as such, it has spread across multiple continents. 2-4The World Health Organization designated BA.2.75 as a "variant of concern lineage under monitoring."Of additional concern, BA.2.75 may differ antigenically from BA.2.The receptor-binding domain of the spike (S) protein of SARS-CoV-2 is capable of inducing neutralizing antibodies and is the major target for monoclonal antibodybased therapy.BA.2, as compared with the reference strain Wuhan/Hu-1/2019, possesses 16 amino acid substitutions in the receptor-binding domain; BA.2 and BA.2.75 share 14 of these 16 substitutions.However, BA.2.75 possesses 4 amino acid changes in the receptor-binding domain (i.e., G339H, G446S, N460K, and the wild-type amino acid at position 493) that differ from those in BA.2, which suggests that the monoclonal antibodies authorized for emergency use by the Food and Drug Administration (FDA) may be less effective against BA.2.75 than against other SARS-CoV-2 strains and variants.To assess the efficacy of authorized therapeutic monoclonal antibodies against BA.2.75, we examined their neutralizing abilities against the BA.2.75 variant hCoV-19/Japan/TY41-716/2022 (TY41-716), which was isolated from a person traveling from India to Japan.Whole-genome sequencing of TY41-716 revealed that it possesses nine amino acid changes (K147E, W152R, F157L, I210V, G257S, D339H, G446S, N460K, and Q493
Adipose Tissue Remodeling in Pathophysiology
Authors: Christopher Auger, Shingo Kajimura
Journal: Annual Review of Pathology Mechanisms of Disease (2022)

Rather than serving as a mere onlooker, adipose tissue is a complex endocrine organ and active participant in disease initiation and progression. Disruptions of biological processes operating within adipose can disturb healthy systemic physiology, the sequelae of which include metabolic disorders such as obesity and type 2 diabetes. A burgeoning interest in the field of adipose research has allowed for the elucidation of regulatory networks underlying both adipose tissue function and dysfunction. Despite this progress, few diseases are treated by targeting maladaptation in the adipose, an oft-overlooked organ. In this review, we elaborate on the distinct subtypes of adipocytes, their developmental origins and secretory roles, and the dynamic interplay at work within the tissue itself. Central to this discussion is the relationship between adipose and disease states, including obesity, cachexia, and infectious diseases, as we aim to leverage our wealth of knowledge for the development of novel and targeted therapeutics.
Biomaterials for <i>Helicobacter pylori</i> therapy: therapeutic potential and future perspectives
Authors: Yongkang Lai, Wei Wei, Yiqi Du, Jie Gao, Zhaoshen Li
Journal: Gut Microbes (2022)

Helicobacter pylori (H. pylori) is the main cause of gastric adenocarcinoma. However, the traditional antibiotic treatment of H. pylori is limited due to increased antibiotic resistance and low efficacy; low drug delivery efficiency and difficulties in eradicating H. pylori that is present intracellularly or in biofilms cause further setbacks. Biomaterials that can protect drugs against stomach acid, target lesions, control drug release, destroy biofilms, and exhibit unique antibacterial mechanisms and excellent biocompatibility have emerged as attractive tools for H. pylori eradication, particularly for drug-resistant strains. Herein, we review the virulence mechanisms, current drug treatments, and antibiotic resistance of H. pylori strains. Furthermore, recent advances in the development of biomaterials, including nanoparticles (such as lipid-based nanoparticles, polymeric nanoparticles, and inorganic nanoparticles), microspheres, and hydrogels, for effective and precise therapy of H. pylori and different types of therapeutic mechanisms, as well as future perspectives, have also been summarized.